Abstract A023: Rewiring host immunity with cytotoxic agents and tumor targeted costimulatory bispecific antibodies potentiate polyclonal T cell antitumor immunity

Abstract Cytotoxic agents, including chemotherapy and antibody drug conjugates (ADCs), have revolutionized cancer treatment but are often limited by drug resistance, toxicity, and insufficient engagement of anti-tumor immunity. Consequently, understanding how cytotoxic drugs can safely combine with novel immunotherapies and the cellular mechanisms driving effective anti-tumor immunity remains a priority. Here, we report that tumor-associated antigen (TAA)-targeted CD28 agonistic antibodies (TAAxCD28) synergistically enhance ADCs and chemotherapy efficacy by rewiring innate and adaptive immunity. Using humanized murine immunocompetent models, we demonstrate that combining a standard of care ADC with TAAxCD28 antibodies achieves complete tumor rejection and durable immune memory in tumors resistant to ADC monotherapy. Similarly, TAAxCD28 bispecific antibodies synergize with systemic chemotherapy to improve tumor growth control and survival. These strategies enable lower doses or reduced administration frequency of cytotoxic drugs, achieving superior anti-tumor efficacy while mitigating systemic toxicity. Mechanistic studies show that TAAxCD28 antibodies activate a TCR-restricted pool of naïve/stem-like tumor-infiltrating CD8+ T cells. Adding ADCs or chemotherapy sustain T cell activation while maintain a diversified pool of CD8+ T effector cells necessary for efficient tumor control. Combination synergy is further mediated by cytotoxic drug-induced reprogramming of the tumor microenvironment, activating dendritic cells (DCs) and immunostimulatory monocytes, which upregulate costimulatory molecules and proinflammatory cytokines amplifying T cell responses to TAAxCD28 antibodies. These findings highlight combining approved cytotoxic agents with TAAxCD28 antibodies as a novel clinical strategy to overcome treatment resistance and improve outcomes in patients with refractory cancers. Citation Format: Qiaozhi Wei, Dylan Kwart, Wei-Yi Cheng, Kamilah Ryan, Bei Wang, Dimitris Skokos. Rewiring host immunity with cytotoxic agents and tumor targeted costimulatory bispecific antibodies potentiate polyclonal T cell antitumor immunity [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A023.